E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibromyalgia, also known as FMS, is a common systemic rheumatologic disorder estimated to affect 2 to 4% of the population [51, 50]. Fibromyalgia is associated with a reduced threshold for pain, generally identified by an increased sensitivity to pressure at particular points on the body, and is often accompanied by fatigue, sleep disturbance, and morning stiffness. Other common symptoms include headache, migraine, variable bowel habits, diffuse abdominal pain, and urinary frequency. |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the efficacy of milnacipran 200 mg/day as compared to placebo in the treatment of the fibromyalgia syndrome in outpatients after a 12-week period of fixed dose exposure. |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy of 200 mg/day of milnacipran to placebo on the time course and durability of response To compare the efficacy of 200 mg/day of milnacipran to placebo on a number of additional secondary endpoints including, but not limited to, fatigue, sleep and mood To establish the safety profile of 200 mg/day of milnacipran in patients with FMS. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
Female and male patients aged 18 - 65 years with a diagnosis of fibromyalgia according to the 1990 ACR criteria.Females must be either postmenopausal (no menses for at least 1 year) or status-post hysterectomy, oophorectomy (bilateral), tubal ligation or, if of childbearing potential, must have a negative urine pregnancy test prior randomisation, and be using a medically acceptable form of contraception for about two months before the inclusion in this study (i.e., hormonal birth control, IUD, double barrier [male condom, female condom, diaphragm] or a barrier method plus a spermicidal agent [contraceptive foam, jelly, or cream]). The patient should be advised to continue the contraception one month after the intake of the last dose of study treatment.Patients must have the ability to give informed consent.Patients must be willing to withdraw from CNS-active therapies commonly used for FMS, including anti-depressants, anti-convulsants, mood stabilizers, opioids whatever the route of administration.Patients must be willing to discontinue treatment with transcutaneous electrical nerve stimulation, trigger point, tender point or joint injections, acupuncture, and anaesthetics (ketamine).Patients must be able to read and understand the text in local language on the Patient Electronic Diary (PED) screen.Patients must be able to hear and respond to the PED audible prompts.Patients must be willing and able to use a PED device daily for a minimum of 22 weeks and 2 days.Patients must not miss greater than 4 PED morning reports during the relevant days of the baseline period (the relevant days are defined as the 14 days prior to Visit 3 during the time interval between Visit 2 and Visit 3). The baseline period must be a minimum of 14 days.Patients must have an average VAS intensity pain scale recording (based on the electronic diary daily pain recall) of at least 40 or more on a 0-100 scale at the end of the baseline period. The baseline period must be a minimum of 14 days. |
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E.4 | Principal exclusion criteria |
Severe psychiatric illness and significant risk of suicide. Patients suffering from a current major depressive episode (MDE-current), or a generalized anxiety disorder (GAD). Patients abusing of alcohol, benzodiazepines or other drugs, substances (cannabis) as defined by the MINI performed by trained staff. Patients with a positive urine drug screen for benzodiazepines and opiates will not be included.Any history or behavior that would, in the Investigator’s estimation, prohibit compliance for the duration of the study.Patients with myocardial infarction within the past 24 months, active cardiac disease (American Heart Association Functional Class 2, 3 or 4), congestive heart failure, hemodynamically significant valvular heart disease (including patients with a prosthetic heart valve), and/or clinically significant cardiac rhythm or conduction abnormalities and/or unstable or uncontrolled hypertension.Patients with pulmonary dysfunction or severe chronic obstructive pulmonary disease that, in the Investigator’s judgment, could interfere with the study participation and completion.Patients with evidence of active liver disease (levels of AST, ALT and/or alkaline phosphatase >1.5x the upper limit of the normal range for the laboratory performing the test).Patients with renal impairment (creatinine > 1.3x the upper limit of the normal range for the laboratory performing the test, adjusted for patient gender, age and lean body weight).Patients with documented systemic autoimmune disease.Chronic inflammatory rheumatoid disease.Patients with current systemic infection.Epileptic patients.Patients with active cancer, (except basal cell carcinoma), or patients currently undergoing therapy for cancer. Patients with a current life expectancy less than one year.Patients with sleep apnea severe enough that, in the Investigator‘s opinion, it would interfere with interpretation of changes in sleep habits. In addition, patients requiring use of CPAP devices are not eligible for the study.Patients with active peptic ulcer, inflammatory bowel disease.Patients with unstable endocrine disease, including unstable diabetes or thyroid disease. Disorders that have been stable under treatment for the preceding 3 months will be acceptable. Male patients with prostatic enlargement or other genito-urinary disorders, who might be at significant risk of dysuria and/or urinary retention when taking agents with noradrenaline re-uptake inhibition properties.Pregnant or breastfeeding females patients.Patients who have received treatment with an experimental agent within the last 30 days.Patients who are receiving concomitant therapy with MAO-A or -B inhibitors, tricyclics, tetracyclics, SSRIs agents, NARIs agents, SNRIs agents or alpha-agonists, anticonvulsants (phenytoin), dopamine agonists, or muscle relaxants.Patients who are receiving concomitant therapy with metabolic enzyme inhibitors (i.e., cimetidine) and enzyme inducers (including phenytoin and phenobarbital), oral anticoagulants (warfarin), type 1C antiarrhythmics (propafenone, flecainide, encainide).Patients who are receiving concomitant therapy with epinephrine, norepinephrine (alpha and beta sympathomimetics) especially when given by parenteral route.Statines if not stable for 4 weeks prior to the randomisation.Patients with concurrent usage of hypericum, SAMe, melatonine, or DHEA.Patients with concurrent usage of digitalis (digoxin) preparations.Patients with concurrent usage of centrally acting analgesics, including tramadol, codeine, dextropropoxyphene and other opioids or opiates.Patients with concurrent usage of systemic steroids by oral, IV or IM route. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Efficacy: Primary variables: Daily 24 h Recall Pain Score and Patient Global Impression of Change (PGIC).· Misc. status assessments: periodically, as described in the schedule of evaluations: Beck Depression Inventory BDI, State Trait Anxiety Inventory (STAI) sleep quality scale (MOS), and sexual dysfunction (ASEX).· FMS Status Assessments: Fibromyalgia Impact Questionnaire (FIQ total and FIQ subscores), Pain threshold, Pain drawing, Multiple Ability Self-report Questionnaire (MASQ, cognitive function), the Multidimensional Health Assessment Questionnaire (MDHAQ), the Multi-dimensional Fatigue Inventory (MFI), FS-36 PCS subscore (assessment of function over time), Patient Global Disease Status, Patient Global Therapeutic BenefitElectronic diary assessments include morning report pain (current and 24-hour recall,), evening report pain (current pain), overall pain last week (weekly report Friday evening), study medications taken (morning and evening report), concomitant treatment (evening report for the last 24 hours), overall fatigue VAS and sleep VAS in the last week (weekly report on Friday evening), PGIC and FIQ during on site visits. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The date of the last visit of the last patient undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |